NOTICE: Applications submitted in response to this
Funding Opportunity Announcement (FOA) for Federal assistance must be submitted
electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424
(R&R) Application Guide.

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read
in conjunction with the application guidelines included with this announcement
in Grants.gov/Apply
for Grants (hereafter called Grants.gov/Apply).

A registration process
is necessary before submission and applicants are highly encouraged to start
the process at least four (4) weeks prior to the grant submission date. See Section IV.

This funding opportunity announcement
(FOA) solicits (R01) grant applications from
applicant organizations that propose to develop and pilot test innovative
interventions to remediate
age-related cognitive decline. These pilot tests are not expected to fulfill
criteria for full-scale clinical trials but should help establish the feasibility and likely effect sizes of potential
interventions. The interventions developed should be amenable for testing in a
randomized clinical trial (RCT).

Purpose.The
purpose of this FOA is to identify new candidate interventions for age-related cognitive decline that would be appropriate for
future testing in a randomized clinical trial (RCT).

Mechanism
of Support.This Funding
Opportunity Announcement (FOA) will utilize the R01 grant mechanism with an exceptional duration (up to three years). The budget shall not
exceed $175,000 in direct costs per year or $525,000 for a three-year duration.

Funds
Available and Anticipated Number of Awards. The NIA anticipates support of up to
$785,000 in FY2009 for applications responsive to this announcement to allow award of 3-4 R01s. Awards issued under this
FOA are contingent upon the availability of funds and the submission of a
sufficient number of meritorious applications.Because
the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and
duration of each award will also vary. The total amount awarded and the number
of awards will depend upon the numbers, quality, duration, and costs of the
applications received.

Budget and
Project Period.The
total project period for an application submitted in response to this funding
opportunity may not exceed three years. Direct costs are limited to $525,000
over a three-year period, with no more than $175,000 in direct costs allowed in
any single year.At this time, it
is not known if this FOA will be reissued.

Eligible Project Directors/Principal Investigators (PDs/PIs). IncludeIndividuals with the skills,
knowledge, and resources necessary to carry out the proposed research are
invited to work with their institution/organization to develop an application
for support. Individuals from underrepresented racial and ethnic groups as well
as individuals with disabilities are always encouraged to apply for NIH
support.

Number
of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the
application.

Number of Applications. Applicants may submit more than one
application, provided each application is scientifically distinct.

Resubmissions.Resubmission applications are not permitted in
response to this FOA.

Renewals.Renewal applications are not permitted in response to
this FOA.

The
NIA, working in part with funds contributed by the McKnight Brain Research
Foundation (http://www.tmbrf.org) in conjunction with the Foundation for NIH (FNIH) (http://www.fnih.org),invites
applications to develop new interventions to prevent or remediate age-related
cognitive decline. As described below, previous
efforts to design and implement such interventions have had modest success
overall. These efforts and additional basic research into cognitive aging,
have, however, pointed out new opportunities for approaches that, especially in combination, may have considerable promise.

The primary goal of
this FOA is to support the initial development and pilot testing of behavioral
interventions in order to establish their feasibility, likely effect sizes, and
their immediate and short-term (one year) efficacy.
Development of these interventions should directly lead to new randomized
clinical trials (RCTs) although these pilot trials do not need to be RCTs. It
should also be noted that the interventions being sought are for the treatment
of individuals who are experiencing age-related
cognitive decline rather than Mild Cognitive Impairment (MCI) or dementia (see,
e.g., Kelly and Petersen, 2007 for a recent review). The secondary goals of
this FOA are to encourage the broad comparability of the interventions that are designed and to encourage greater
interaction among researchers who are developing cognitive interventions. To
meet the comparability goal, responsive applications will recruit populations
with broadly similar demographic characteristics and
eligibility, and may employ a small common “core” battery of evaluations in
addition to any other investigator-specified evaluations at three time points:
pre-intervention, post-intervention, and a one year follow-up. To encourage
greater interactions among investigators, the NIA
will sponsor annual investigator meetings for the grantees supported by this
FOA where preliminary results may be presented and shared.

2.
Background

Age-related cognitive
decline exclusive of dementia will affect most older
individuals to some extent and has a direct impact on their independence and
vitality. As briefly reviewed below, cognitive training, physical exercise,
enhancement of self-efficacy, social engagement, diet, environmental
enrichment, and stress reduction all have positive
effects on cognition. It should be noted that the quality of this evidence
varies from strong (randomized clinical trials in humans) through suggestive
(most epidemiological evidence) to theoretical or anecdotal accounts. The major
purpose of this FOA is to take insights from previous
work in cognitive aging and convert them into feasible intervention strategies
that could be tested in randomized clinical trials.

Among human clinical
trials, the ACTIVE project (Ball et al, 2002, Willis et
al., 2006) stands out, and has established that targeted cognitive training has
beneficial effects on targeted functions that last at least five years. Despite
this success, there is not yet any intervention that has been demonstrated to
lead to significant transfer across cognitive domains
or significant and immediate positive impacts on every day functioning in a
randomized clinical trial. Some impressive and suggestive work has been
published using animal models, notably recent studies of how combined interventions including environmental enrichment and
dietary changes can have more strongly positive effects than either
intervention alone (Milgram et al., 2005). Interestingly, combined intervention
approaches have only been rarely tried in human studies.

A recent (June 2007)
special issue of The Journal of Gerontology, based on a March 2004 NIA
workshop, includes discussions of how sustainable delay of cognitive decline
and improvement in cognitive function in older adults might require new
approaches (Elias & Wagster, 2007). Among
behavioral approaches, suggestions have been offered for how social engagement
(e.g., Stine-Morrow, 2007), exercise (Colcombe & Kramer, 2003),
self-monitoring (Dunlosky et al., 2007), and non-traditional approaches (Park
et al., 2007) may enhance cognition. Although a much
broader array of potential intervention strategies is available today than
previously, it is also clear that the next generation of interventions to
remediate age-related cognitive decline will need to address four main challenges that have not been fully addressed
by the current state of the art.

The first challenge is
that existing interventions have often had relatively modest effect sizes on
the primary (trained) outcomes. For example, the initial benefit of the ACTIVE memory intervention was only .26 standard
deviations, and only 26 percent of treated participants showed reliable
improvement over baseline (Ball et al., 2002). In most situations that do not
involve ceiling effects, the size of the initial improvement
in an intervention will be the limit of its longer-term effectiveness. A prime
purpose of this FOA is to establish likely effect sizes for a variety of novel
interventions.

The second challenge
for specifically cognitive interventions is that transfer
of training between trained and untrained cognitive abilities has been
extremely weak at best. Although substantial transfer of training may be
occasionally seen (see, e.g., Singley and Anderson, 1989 for specific examples), this has not been consistently seen in any intervention targeting age-related
cognitive decline. Interestingly, it is well-known that there is substantial
protective effect of earlier education on general cognitive ability in old age
(e.g., Au et al., 2004), but it is unknown whether
education programs could have a beneficial effect in old age.

The third challenge
faced by interventions is previous interventions have had only very limited
effects on performance-related measures of everyday functioning or
(instrumental) activities of daily living. Although
this may simply reflect the difficulty of obtaining “distant transfer”, this
pattern may also suggest the need to consider interventions more grounded in
everyday experience. Preliminary data from the Senior Oddysey project (Stine-Morrow et al., 2007) and the larger Experience Corps
Project (Fried et al., 2004) are encouraging in this regard.

The fourth challenge
faced by possible interventions is related to the initiation and appropriate
maintenance of treatment. Age-related cognitive
decline might best be viewed as a chronic condition requiring ongoing
treatment, although these approaches have been under-studied. As a concrete
example, aerobic exercise has significant short-term effects on cognition in
older adults, notably executive functioning (Colcombe
& Kramer, 2003). Neither initiation nor maintenance of exercise programs in
the elderly are without significant difficulties, however. Applications to this
FOA are encouraged to address initiation and maintenance issues related to continued cognitive training or behavior change. (For
discussion of these issues with respect to non-cognitive interventions see
Prohaska et al., 2006 or Powell et al., 2007).

It is not expected
that the pilot interventions for this FOA will be able to address each of these four challenges with equal success. Applications
that are responsive to this FOA should, however, make a convincing case that
the proposed intervention is likely to yield effects that are larger, more
wide-ranging, or more permanent than previous
approaches, and that it is worthy of testing in a randomized clinical trial .

The goal of this
FOA is to identify new interventions for possible testing in a full-scale
randomized clinical trial. In order to compare and evaluate the likelihood of success of these pilots, it is important that
subject populations be relatively comparable between studies and that similar
outcomes be measured. Applications are free to add additional measures.

Applicants
should propose pre-screening tools (such as the MMSE
(Folstein et al., 1975) and the SF-36 (Ware, Snow, Kosinski, & Gandek,
1993)) to identify a sample retaining normal cognitive function and health good
enough to allow them to be evaluated one-year post intervention. The sample
ages should be justified relative to the specific
intervention proposed. Overall, to the extent possible, the sample tested
should reflect the demographic characteristics of healthy, older individuals.

Outcomes measures of daily function,
auditory memory, visual memory, and reasoning or
executive functioning must be included and administered pre-intervention,
post-intervention, and at least one follow-up point. If only one follow-up data
point is collected, it should be one year following the onset of the intervention. Measures of daily function must include ADLs and IADLs
(Lawton and Brody, 1969). Measures of the specific cognitive functions should
rely on published tests or test batteries with age-appropriate norms.

NIA staff will arrange
an early (year zero) meeting of grantees to agree on
a small core set of measurement instruments to be used across studies and
interventions. A primary goal of these projects should be to establish likely
effect sizes for specific interventions. For this reason, projects do not need to be powered to detect any specified criterion
effect size,

but power analyses
should be supplied to indicate what effect sizes should be detectable given the
sample size proposed.

3.
Scope

The scope of possible
intervention projects under this initiative is being
left deliberately broad. It should, however, be noted that applications
proposing drug-based approaches are not appropriate to this FOA, and are
targeted through other NIA programs.

This FOA is designed
to support both unitary and combined interventions
for cognitive improvement. It is notable that very few cognitive intervention
programs have sought to combine multiple approaches, and it is not well
understood how the effect sizes of such combined interventions might be
modified by the combination. One possible and
desirable outcome of a combined intervention involving cognitive training
programs is that such approaches will cause greater gains in cognition because
multiple domains are trained. Combinations of cognitive training and other treatment modalities (e.g., exercise or diet) would seek
both to provide a direct benefit and to enhance the value of cognitive
training. The area of combined interventions for cognitive improvement is an
emerging area of research where more work is needed,
and applications that provide strong theoretical justification for a proposed
combined intervention using well-characterized approaches are especially
encouraged.

Applications
responsive to this FOA, however, do not need to propose interventions that include cognitive training. Exercise has been shown to be
associated with reduced risk for incident dementia (Larson et al., 2006) and
cardiovascular fitness overall is associated with enhanced cognitive outcomes
and changes in attentional networks at the neural
level (Colcombe et al., 2004). Other lifestyle or engagement interventions are
also invited, as are interventions based on or including the enhancement of
self-efficacy or self-monitoring (e.g., Dunlosky et al., 2007, West et al.,
2007). Projects combining behavioral with
nutraceutical or dietary interventions (reviewed by, e.g., Luchsinger and
Mayeux, 2004) are also suitable, although some of the more obvious approaches
for nutraceuticals have already been tried in some randomized clinical trials (e.g., McNeill et al., 2007). Dietary supplementation with
natural foods, however, in combination with nutraceuticals such as omega-3
fatty acids have been successfully applied to older dogs, especially when
combined with environmental enrichment (Milgram et al.,
2005).

Investigators are also
encouraged to investigate how responses to their pilot interventions may be
affected by the cognitive or non-cognitive profiles of their participants. In
particular, individual differences in response to interventions may be related to personality factors (e.g., self-efficacy,
sense of control, motivation, affective state, conscientiousness) or
sociocultural or demographic factors (e.g., socioeconomic status, education,
ethnicity). Proposed interventions are invited to address
is the role of individual differences in mediating or moderating intervention
adherence and outcomes. For example there is evidence that evidence
demonstrates that memory self-efficacy is correlated with improvements in
memory performance (e.g., Dunlosky et al., 2007), and
it would be useful to know whether self-efficacy mediates or moderates
improvements in cognitive function due to a particular intervention.

This FOA will use theR01 award mechanism. The Project Director/Principal
Investigator (PD/PI) will be solely responsible for planning, directing,
and executing the proposed project.

This FOA uses “Just-in-Time” information concepts (see SF424 (R&R)
Application Guide). It also uses the modular as well as the
non-modular budget formats (seehttp://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, a U.S. organization submitting an application with direct costs
in each year of $250,000 or less (excluding consortium Facilities and
Administrative [F&A] costs) must use the PHS398 Modular Budget component.

U.S. applicants requesting more than
$250,000 in annual direct costs and all Foreign applicants must complete and
submit budget requests using the Research & Related Budget component.

2.
Funds Available

Because the
nature and scope of the proposed research will vary from application to
application, it is anticipated that the size and duration of each award will
also vary. Although the financial plans of the NIA provide support for this
program, awards pursuant to this funding opportunity are contingent upon the
availability of funds and the submission of a sufficient number of meritorious
applications.

As an
exception to the usual guidelines for R01 applications, the total project period for an application submitted in response
to this funding opportunity may not exceed 3 years.

Direct costs are
limited to $525,000 over a three-year period, with no more than $175,000 in
direct costs allowed in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs
limitation of $525,000 for the combined three-year award period.

The NIA anticipates
awarding up to $785,000 in FY 2009 to fund three or four applications.

Facilities
and Administrative (F&A) costs requested by consortium participants are not
included in the direct cost limitation. See NOT-OD-05-004.

The decision of whether to
apply for a grant with a single PD/PI or multiple PDs/PIs grant is the
responsibility of the investigators and applicant organizations and should be
determined by the scientific goals of the project. Applications for grants with
multiple PDs/PIs will require additional information, as outlined in the
instructions below. The NIH review criteria for approach, investigators, and
environment have been modified to accommodate applications involving either a
single PD/PI or multiple PDs/PIs. When considering the multiple PD/PI option,
please be aware that the structure and governance of the PD/PI leadership team
as well as the knowledge, skills and experience of the individual PDs/PIs will
be factored into the assessment of the overall scientific merit of the
application. Multiple PDs/PIs on a project share the authority and
responsibility for leading and directing the project, intellectually and
logistically. Each PD/PI is responsible and accountable to the grantee
organization, or, as appropriate, to a collaborating organization, for the
proper conduct of the project or program, including the submission of required
reports. For further information on multiple PDs/PIs, please seehttp://grants.nih.gov/grants/multi_pi.

Applicants are not
permitted to submit a resubmission application in response to this FOA.

Renewal applications
are not permitted in response to this FOA.

Applicants may submit
more than one application, provided each application
is scientifically distinct.

Section IV. Application and Submission Information

To
download a SF424 (R&R) Application Package and SF424 (R&R) Application
Guide for completing the SF424 (R&R) forms for this FOA, use the “Apply for
Grant Electronically” button in this FOA or link to http://www.grants.gov/Apply/ and follow
the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

The individual(s) designated as
PDs/PIs on the application must be registered also in the NIH eRA Commons. In the case of multiple PDs/PIs, all PDs/PIs must be registered and be assigned
the PI role in the eRA Commons prior to the submission of the application.

Each PD/PI must
hold a PD/PI account in the Commons. Applicants should not share a Commons account for both an Authorized Organization
Representative/Signing Official (AOR/SO)
role and a PD/PI role; however, if they have both a PD/PI role and an NIH
Internet Assisted Review (IAR) role, both roles should exist under one Commons account.

When multiple PDs/PIs are
proposed, all PDs/PIs at the applicant organization must be affiliated with
that organization. PDs/PIs located at another institution need not be
affiliated with the applicant organization, but must be affiliated with their
own organization to be able to access the Commons.

This registration/affiliation must
be done by the AOR/SO or his/her designee who is already registered in the Commons.

Both the PDs/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the
application image.

Note that if a PD/PI is
also an NIH peer reviewer with an Individual DUNS and CCR registration, that
particular DUNS number and CCR registration are for the individual reviewer
only. These are different than any DUNS number and CCR registration used by an
applicant organization. Individual DUNS and CCR registration should be used
only for the purposes of personal reimbursement and should not be used on any
grant applications submitted to the Federal Government.

Several of the steps of
the registration process could take four weeks or more. Therefore, applicants
should immediately check with their business official to determine whether
their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept
electronic applications only from organizations that have completed all
necessary registrations.

1. Request Application Information

Applicants must download
the SF424 (R&R) application forms and the SF424 (R&R) Application Guide
for this FOA through Grants.gov/Apply.

Note:
Only the forms package directly attached to a specific FOA can be used. You
will not be able to use any other SF424 (R&R) forms (e.g., sample forms,
forms from another FOA), although some of the "Attachment" files may
be useable for more than one FOA.

Prepare all
applications using the SF424 (R&R) application forms and in accordance with
the SF424 (R&R) Application Guide for this FOA
through Grants.gov/Apply.

The SF424 (R&R)
Application Guide is critical to submitting a complete and accurate application
to NIH. Some fields within the SF424 (R&R) application components, although
not marked as mandatory, are required by NIH (e.g., the “Credential” log-in
field of the “Research & Related Senior/Key Person Profile” component must
contain the PD/PI’s assigned eRA Commons User ID). Agency-specific
instructions for such fields are clearly identified in the Application Guide.
For additional information, see “Frequently Asked Questions – Application
Guide, Electronic
Submission of Grant Applications.”

The SF424 (R&R)
application has several components. Some components are required, others are
optional. The forms package associated with this FOA in Grants.gov/APPLYincludes all applicable components, required and optional. A completed
application in response to this FOA includes the data in the following
components:

Proposed research should provide special opportunities
for furthering research programs through the use of unusual talent, resources,
populations, or environmental conditions in other countries that are not
readily available in the United States (U.S.) or that augment existing U.S. resources.

SPECIAL
INSTRUCTIONS

Applications with
Multiple PDs/PIs

When
multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the
"Contact” PI, who will be responsible for all communication between the
PDs/PIs and the NIH, for assembling the application materials outlined below,
and for coordinating progress reports for the project. The contact PD/PI must
meet all eligibility requirements for PD/PI status in the same way as other
PDs/PIs, but has no other special roles or responsibilities within the project
team beyond those mentioned above.

Information
for the Contact PD/PI should be entered in item 15 of the SF424 (R&R) Cover
component. All other PDs/PIs should be listed in the Research &
Related Senior/Key Person component and assigned the project role of
“PD/PI.” Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the
“Credential” field of the Research & Related Senior/Key Person
component. Failure to include this data field will cause the application
to be rejected.

All projects
proposing Multiple PDs/PIs will be required to include a new section describing
the leadership plan approach for
the proposed project.

Multiple
PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new
section of the research plan, entitled “Multiple PD/PI Leadership Plan”
[Section 14 of the Research Plan Component in the SF424 (R&R)], must be
included. A rationale for choosing a multiple PD/PI approach should be
described. The governance and organizational structure of the leadership team
and the research project should be described, and should include communication
plans, process for making decisions on scientific direction, and procedures for
resolving conflicts. The roles and administrative, technical, and
scientific responsibilities for the project or program should be delineated for
the PDs/PIs and other collaborators.

If
budget allocation is planned, the distribution of resources to specific
components of the project or the individual PDs/PIs should be delineated in the
Leadership Plan. In the event of an award, the requested allocations may be
reflected in a footnote on the Notice of Award (NoA).

Applications Involving a
Single Institution

When all PDs/PIs are
within a single institution, follow the instructions contained in the SF424
(R&R) Application Guide.

Applications Involving
Multiple Institutions

When
multiple institutions are involved, one institution must be designated as the
prime institution and funding for the other institution(s) must be requested
via a subcontract to be administered by the prime institution. When submitting
a detailed budget, the prime institution should submit its budget using the
Research & Related Budget component. All other institutions should
have their individual budgets attached separately to the Research & Related
Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R)
Application Guide for further instruction regarding the use of the subaward
budget form.

When
submitting a modular budget, the prime institution completes the PHS398 Modular
Budget component only. Information concerning the consortium/subcontract
budget is provided in the budget justification. Separate budgets for each
consortium/subcontract grantee are not required when using the Modular budget
format. See Section 5.4 of the Application Guide for further instruction
regarding the use of the PHS398 Modular Budget component.

Prospective
applicants are asked to submit a letter of intent that includes the following
information:

Descriptive title of proposed research.

Name, address, and telephone number of the
PD(s)/PI(s).

Names of other key personnel.

Participating institutions.

Number and title of this funding opportunity.

Although
a letter of intent is not required, is not binding, and does not enter into the
review of a subsequent application, the information that it contains allows IC
staff to estimate the potential review workload and plan the review.

In order to expedite the
review, applicants are requested to notify the NIAReferral Office by email (Vemuri@nia.nih.gov) when the application has been
submitted. Please include the FOA number and title, PD/PI name, and
title of the application.

3.C.
Application Processing

Applications may be submitted on or after the opening date and must be
successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant
institution/organization) on the application due date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the due date(s)
and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully
submitted through Grants.gov, any errors have been addressed, and the assembled
application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing
Official (AOR/SO) have two weekdays (Monday – Friday, excluding Federal
holidays) to view the application image to determine if any further action is
necessary.

If everything is acceptable, no
further action is necessary. The application will automatically
move forward to the Division of Receipt and Referral in the Center for
Scientific Review for processing after two weekdays, excluding Federal holidays.

Prior to the submission deadline, the AOR/SO can “Reject” the assembled application and submit a changed/corrected application within
the two-day viewing window. This option should be used if it is determined
that some part of the application was lost or did not transfer correctly
during the submission process, the AOR/SO will have the option to “Reject”
the application and submit a Changed/Corrected application. In these cases, please contact the eRA
Help Desk to ensure that the issues are addressed and corrected. Once
rejected, applicants should follow the instructions for correcting errors
in Section 2.12, including the requirement for cover letters on late
applications. The “Reject” feature should also be used if
you determine that warnings are applicable to your application and need to
be addressed now. Remember, warnings do not stop further application
processing. If an application submission results in warnings (but no
errors), it will automatically move forward after two weekdays if no
action is taken. Some warnings may need to be addressed later
in the process.

If
the two-day window falls after the submission deadline, the AOR/SO will have the option to “Reject” the application if, due to an eRA Commons or Grants.gov
system issue, the application does not correctly reflect the submitted
application package (e.g., some part of the application was lost or didn’t
transfer correctly during the submission process). The AOR/SO should first
contact the eRA Commons Helpdesk to confirm the system error, document the issue, and determine the best course
of action. NIH will not penalize the applicant for an eRA Commons or Grants.gov system issue.

If
the AOR/SO chooses to “Reject” the image after the submission deadline for a
reason other than an eRA Commons or Grants.gov system failure, a
changed/corrected application still can be submitted, but it will be subject to
the NIH
late policy guidelines and may not be accepted. The reason for this delay
should be explained in the cover letter attachment.

Both
the AOR/SO and PD/PI will receive e-mail notifications when the application is
rejected or the application automatically moves forward in the process after
two weekdays.

Upon receipt, applications will be evaluated for
completeness by the CSR and responsiveness by the IC. Incomplete and
non-responsive applications will not be reviewed.

There
will be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR/SO receives the Grants.gov acknowledgments. The AOR/SO and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific
Review Group is also in the Commons.

Note: Since email can be
unreliable, it is the responsibility of the applicant to check periodically on
the application status in the Commons.

The
NIH will not accept any application in response to this funding opportunity
that is essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application. However, when a previously
unfunded application, originally submitted as an investigator-initiated
application, is to be submitted in response to a funding opportunity, it is to
be prepared as a NEW application. That is, the application for the funding
opportunity must not include an “Introduction” describing the changes and
improvements made, and the text must not be marked to indicate the changes from
the previous unfunded version of the application.

All NIH awards are
subject to the terms and conditions, cost principles, and other considerations
described in the NIH Grants Policy Statement.

Pre-award costs are allowable. A grantee may, at its
own risk and without NIH prior approval, incur obligations and expenditures to
cover costs up to 90 days before the beginning date of the initial budget
period of a new or renewal award if such costs: 1) are necessary to conduct the
project, and 2) would be allowable under the grant, if awarded, without NIH
prior approval. If specific expenditures would otherwise require prior
approval, the grantee must obtain NIH approval before incurring the cost. NIH
prior approval is required for any costs to be incurred more than 90 days
before the beginning date of the initial budget period of a new or renewal
award.

The incurrence of pre-award costs in anticipation of a
competing or non-competing award imposes no obligation on NIH either to make
the award or to increase the amount of the approved budget if an award is made
for less than the amount anticipated and is inadequate to cover the pre-award
costs incurred. NIH expects the grantee to be fully aware that pre-award costs
result in borrowing against future support and that such borrowing must not
impair the grantee's ability to accomplish the project objectives in the
approved time frame or in any way adversely affect the conduct of the project
(see theNIH
Grants Policy Statement).

The
applicant organization must include its DUNS number in its Organization Profile
in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional
information, see “Frequently Asked Questions – Application Guide, Electronic
Submission of Grant Applications.”

PHS398
Research Plan Component Sections

Page
limitations of the PHS398 Research Plan component must be followed as outlined
in the SF424 (R&R) Application Guide. While each section of the Research
Plan component needs to be uploaded separately as a PDF attachment, applicants
are encouraged to construct the Research Plan component as a single document,
separating sections into distinct PDF attachments just before uploading the
files. This approach will enable applicants to better monitor formatting
requirements such as page limits. All attachments must be provided to NIH in
PDF format, filenames must be included with no spaces or special characters,
and a .pdf extension must be used.

All
application instructions outlined in the SF424 (R&R) Application Guide are
to be followed, incorporating "Just-in-Time" information concepts,
and with the following additional requirements:

Do not use the Appendix to circumvent the page limitations of
the Research Plan component. An application that does not comply with the
required page limitations may be delayed in the review process.

Investigators’
Annual Meeting

Award recipients
are required to include in their budget funds sufficient to send the principal
investigator(s) and possibly other key project
personnel to each of three annual investigator meetings to be held in Bethesda, Maryland.

Sharing of Participant Characteristics and Screening Instruments

Because the
studies to be supported are pilots for an intended full-scale clinical trial,
participants will be required to share de-identified participation information,
screening tools and outcome measures with other grantees. Investigators should
indicate willingness to share this information in the application.

Resource Sharing Plan(s)

NIH considers
the sharing of unique research resources developed through NIH-sponsored
research an important means to enhance the value and further the advancement of
the research. When resources have been developed with NIH funds and the
associated research findings published or provided to NIH, it is important that
they be made readily available for research purposes to qualified individuals
within the scientific community. If the final
data/resources are not amenable to sharing, this must be explained in the
Resource Sharing section of the application (see http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.)

(b) Sharing Model Organisms: Regardless of
the amount requested, all applications where the development of model organisms
is anticipated are expectedto include a description of a
specific plan for sharing and distributing unique model organisms and related
resources or state appropriate reasons why such sharing is restricted or not
possible (see Sharing
Model Organisms Policy, and NOT-OD-04-042.)

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount
requested, applicants seeking funding for a genome-wide association
study are expected to provide a plan for submission of GWAS data to the
NIH-designatedGWAS data repository, or provide an appropriate
explanation why submission to the repository is not possible. A
genome-wide association study is defined as any study of genetic variation
across the entire genome that is designed to identify genetic associations with
observable traits (e.g., blood pressure or weight) or the presence or absence
of a disease or condition. For further information see Policy for Sharing
of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies
(go to NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.)

Foreign Applications
(Non-Domestic [non-U.S.] Entities)

Indicate how the proposed project has specific
relevance to the mission and objectives of the NIH/IC and has the potential for
significantly advancing the health sciences in the United States.

Section V. Application Review Information

1.
Criteria

Only
the review criteria described below will be considered in the review process.

2. Review and
Selection Process

Applications that are
complete and responsive to this FOA will be evaluated for scientific and technical merit by an appropriate peer review
group convened by NIA and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/),
using the review criteria stated below.

As
part of the scientific peer review, all applications will:

Undergo a
selection process in which only those applications deemed to have the
highest scientific and technical merit, generally the top half of
applications under review, will be discussed and assigned a priority
score;

Receive a
written critique; and

Receive a second level of review by the National Advisory Council on Aging.

Applications
submitted in response to this FOA will compete for available funds with all
other recommended applications submitted in response to this FOA. The following will be
considered in making funding decisions:

Scientific
merit of the proposed project as determined by peer review.

Availability
of funds.

Relevance
of the proposed project to program priorities.

Compliance with the data-sharing policy described
above.

The goals of NIH
supported research are to advance our understanding of biological systems, to
improve the control of disease, and to enhance health. In their written
critiques, reviewers will be asked to comment on each of the following criteria
in order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals. Each of these criteria will
be addressed and considered in assigning the overall score, and weighted as
appropriate for each application. Note that an application does not need to be
strong in all categories to be judged likely to have major scientific impact
and thus deserve a meritorious priority score. For example, an investigator may
propose to carry out important work that by its nature is not innovative but is
essential to move a field forward.

Significance:Does this study address an important problem? If
the aims of the application are achieved, how will scientific knowledge or
clinical practice be advanced? What will be the effect of these studies on the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field? Does the intervention that is proposed have the potential
to remediate age-related cognitive decline?

Approach:Are the
conceptual or clinical framework, design, methods, and analyses adequately
developed, well integrated, well reasoned, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics? Is the approach proposed likely to lead to the development
of an intervention that could be tested in a
subsequent clinical trial? For applications designating multiple PDs/PIs, is the
leadership approach, including the designated roles and responsibilities,
governance, and organizational structure, consistent with and justified by the
aims of the project and the expertise of each of the PDs/PIs?

Innovation: Is the project original and innovative? For
example: Does the project challenge existing paradigms or clinical practice;
address an innovative hypothesis or critical barrier to progress in the field?
Does the project develop or employ novel concepts, approaches, methodologies,
tools, or technologies for this area?

Investigators:Are the PD(s)/PI(s) and other key personnel appropriately
trained and well suited to carry out this work? Is the work proposed
appropriate to the experience level of the principal investigator and other
researchers? Do(es) the PD(s)/PI(s) and investigative team bring complementary
and integrated expertise to the project (if applicable)? Does the investigative team included members with expertise in designing,
implementing, and analyzing data from interventions?

Environment: Do(es) the
scientific environment(s) in which the work will be done contribute to the
probability of success? Do the proposed studies benefit from unique features of
the scientific environment, or subject populations, or employ useful
collaborative arrangements? Is there evidence of institutional support?

2.A.
Additional Review Criteria

In addition to
the above criteria, the following items will continue to be considered in the
determination of scientific merit and the rating:

Protection
of Human Subjects from Research Risk: The involvement of human
subjects and protections from research risk relating to their participation in
the proposed research will be assessed. See the “Human Subjects Sections”
of the PHS398 Research Plan component of the SF424 (R&R).

Inclusion of Women and Minorities in Research: The adequacy of plans to
include subjects from both genders and all racial and ethnic groups (and
subgroups), as appropriate for the scientific goals of the research, will be
assessed. Plans for the recruitment and retention of subjects will also be
evaluated. See the “Human Subjects Sections” of the PHS398 Research Plan component
of the SF424 (R&R)

Care and Use of Vertebrate Animals in Research: If vertebrate animals
are to be used in the project, the adequacy of the plans for their care and use
will be assessed. See the “Other Research Plan Sections” of the PHS398 Research
Plan component of the SF424 (R&R).

Biohazards: If materials or procedures are proposed that are potentially
hazardous to research personnel and/or the environment, determine if the
proposed protection is adequate.

2.B. Additional Review Considerations

Budget and
Period of Support: The reasonableness of the proposed budget and the
appropriateness of the requested period of support in relation to the proposed
research may be assessed by the reviewers. The priority score should not be
affected by the evaluation of the budget.

Applications from Foreign Organizations: Whether the project presents special opportunities
for furthering research programs through the use of unusual talent, resources,
populations, or environmental conditions in other countries that are not
readily available in the United States or that augment existing U.S. resources will be assessed.

2.C. Resource Sharing
Plan(s)

When relevant, reviewers will be instructed to comment on the reasonableness of
the following Resource Sharing Plans, or the rationale for not sharing the
following types of resources. However, reviewers will not factor the proposed
resource sharing plan(s) into the determination of scientific merit or priority
score, unless noted otherwise in the FOA. Program staff within the IC will be
responsible for monitoring the resource sharing.

Because this FOA seeks to support the development of interventions that
may be tested in full-scale clinical trials, applicants are expected to share basic (de-identified) information on the
demographic characteristics of their participants as well as the minimally
screening and outcome measures required for applications that are responsive to
this FOA.

3.
Anticipated Announcement and Award Dates

Not applicable.

Section
VI. Award Administration Information

1.
Award Notices

After the peer review of the application
is completed, the PD/PI will be able to access his or her Summary Statement
(written critique) via the NIH eRA Commons.

A formal notification in the form of a Notice of Award
(NoA) will be provided to the applicant organization. The NoA signed by the
grants management officer is the authorizing document. Once all administrative
and programmatic issues have been resolved, the NoA will be generated via email
notification from the awarding component to the grantee business official.

Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the
extent considered allowable pre-award costs. See Section
IV.5., “Funding Restrictions.”

2. Administrative and National Policy Requirements

It should be emphasized that awards made as a result of
this FOA will include Human Subjects and that the research will be considered
Clinical Research as defined by the NIH. Awardees
will be required to have all necessary clearances for the use of human subjects
in place at the time of award.

A final
progress report, invention statement, and Financial Status Report are required
when an award is relinquished when a recipient changes institutions or when an
award is terminated.

Section VII. Agency Contacts

We
encourage your inquiries concerning this funding opportunity and welcome the
opportunity to answer questions from potential applicants. Inquiries may fall
into three areas: scientific/research (program), peer review, and financial or
grants management issues:

Human Subjects
Protection:Federal regulations (45 CFR 46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and others,
and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety
Monitoring Plan:Data and safety monitoring is required for all types
of clinical trials, including physiologic toxicity and dose-finding studies
(Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative
trials (Phase III). Monitoring should be commensurate with risk. The
establishment of data and safety monitoring boards (DSMBs) is required for
multi-site clinical trials involving interventions that entail potential risks
to the participants (“NIH Policy for Data and Safety Monitoring,” NIH Guide
for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:Investigators submitting an NIH application seeking
$500,000 or more in direct costs in any single year are expected to include a
plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).Investigators should seek guidance from their
institutions, on issues related to institutional policies and local
institutional review board (IRB) rules, as well as local, State and Federal
laws and regulations, including the Privacy Rule. Reviewers will consider the
data sharing plan but will not factor the plan into the determination of the
scientific merit or the priority score.

Policy for Genome-Wide
Association Studies (GWAS):NIH is interested in advancing genome-wide association
studies (GWAS) to identify common genetic factors that influence health and
disease through a centralized GWAS data repository. For the purposes of this
policy, a genome-wide association study is defined as any study of genetic
variation across the entire human genome that is designed to identify genetic
associations with observable traits (such as blood pressure or weight), or the
presence or absence of a disease or condition. All applications, regardless of
the amount requested, proposing a genome-wide association study are expected to
provide a plan for submission of GWAS data to the NIH-designated GWAS data
repository, or provide an appropriate explanation why submission to the
repository is not possible. Data repository management (submission and access)
is governed by the Policy for Sharing of Data Obtained in NIH Supported or
Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088.
For additional information, see http://grants.nih.gov/grants/gwas/

Sharing of Model Organisms:NIH is committed to support efforts that encourage
sharing of important research resources including the sharing of model
organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm).
At the same time the NIH recognizes the rights of grantees and contractors to
elect and retain title to subject inventions developed with Federal funding
pursuant to the Bayh-Dole Act (see the NIH
Grants Policy Statement. Beginning October 1, 2004, all investigators
submitting an NIH application or contract proposal are expected to include in
the application/proposal a description of a specific plan for sharing and
distributing unique model organism research resources generated using NIH
funding or state why such sharing is restricted or not possible. This will
permit other researchers to benefit from the resources developed with public
funding. The inclusion of a model organism sharing plan is not subject to a
cost threshold in any year and is expected to be included in all applications
where the development of model organisms is anticipated.

Access to Research Data through the Freedom of
Information Act:The Office of Management and Budget (OMB) Circular
A-110 has been revised to provide access to research data through the Freedom
of Information Act (FOIA) under some circumstances. Data that are: (1) first
produced in a project that is supported in whole or in part with Federal funds;
and (2) cited publicly and officially by a Federal agency in support of an
action that has the force and effect of law (i.e., a regulation) may be
accessed through FOIA. It is important for applicants to understand the basic
scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this funding opportunity in a
public archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.

Inclusion of Women And Minorities in Clinical Research:It is the policy of the NIH that women and members of
minority groups and their sub-populations must be included in all NIH-supported
clinical research projects unless a clear and compelling justification is
provided indicating that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research. This policy results from the
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All
investigators proposing clinical research should read the "NIH Guidelines
for Inclusion of Women and Minorities as Subjects in Clinical Research” (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the SF424 (R&R) application; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a) all
applications or proposals and/or protocols must provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting analyses,
as appropriate, by sex/gender and/or racial/ethnic group differences.

Required Education on the Protection of Human Subject Participants:NIH policy requires education on the protection of
human subject participants for all investigators submitting NIH applications
for research involving human subjects and individuals designated as key
personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):Criteria for Federal funding of research on hESCs can
be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
Only research using hESC lines that are registered in the NIH Human Embryonic
Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). It is the responsibility
of the applicant to provide in the project description and elsewhere in the application
as appropriate, the official NIH identifier(s) for the hESC line(s) to be used
in the proposed research. Applications that do not provide this information
will be returned without review.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators
funded by the NIH must submit or have submitted for them to the National
Library of Medicine’s PubMed Central (see http://www.pubmedcentral.nih.gov/), an
electronic version of their final, peer-reviewed manuscripts upon acceptance
for publication, to be made publicly available no later than 12 months after
the official date of publication. The NIH Public Access Policy is
available at (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html).For more information, see the Public
Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:The Department of Health and Human Services (HHS) issued final modification to the "Standards for Privacy of Individually Identifiable
Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and
Accountability Act (HIPAA) of 1996 that governs the protection of individually
identifiable health information, and is administered and enforced by the HHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information
on the Privacy Rule, including a complete Regulation Text and a set of decision
tools on "Am I a covered entity?" Information on the impact of the
HIPAA Privacy Rule on NIH processes involving the review, funding, and progress
monitoring of grants, cooperative agreements, and research contracts can be
found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs
in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding
must be self-contained within specified page limitations. For publications
listed in the appendix and/or Progress report, Internet addresses (URLs) or
PubMed Central (PMC) submission identification numbers must be used for
publicly accessible on-line journal articles. Publicly accessible on-line
journal articles or PMC articles/manuscripts accepted for publication that are
directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the
Bibliography & References Cited section, the Progress Report Publication
List section, or the Biographical Sketch section of the NIH grant application.
A URL or PMC submission identification number citation may be repeated in each
of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.

Healthy People 2010:The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting
priority areas. This PA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:This program is
described in the Catalog
of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review. Awards are made under the authorization of Sections 301
and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal
Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and
conditions, cost principles, and other considerations described in the NIH Grants
Policy Statement.

The PHS strongly encourages all grant recipients to
provide a smoke-free workplace and discourage the use of all tobacco products.
In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a facility) in
which regular or routine education, library, day care, health care, or early
childhood development services are provided to children. This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.

Loan Repayment Programs:NIH encourages applications for educational loan
repayment from qualified health professionals who have made a commitment to
pursue a research career involving clinical, pediatric, contraception, infertility,
and health disparities related areas. The LRP is an important component of
NIH's efforts to recruit and retain the next generation of researchers by
providing the means for developing a research career unfettered by the burden
of student loan debt. Note that an NIH grant is not required for eligibility
and concurrent career award and LRP applications are encouraged. The periods of
career award and LRP award may overlap providing the LRP recipient with the
required commitment of time and effort, as LRP awardees must commit at least
50% of their time (at least 20 hours per week based on a 40 hour week) for two
years to the research. For further information, please see: http://www.lrp.nih.gov/.